Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial

Long, Georgina V.; Stroyakovskiy, Daniil; Gogas, Helen; Levchenko, Evgeny; Braud, Filippo de; Larkin, James; Garbe, Claus; Jouary, Thomas; Hauschild, Axel; Grob, Jean-Jacques; Chiarion-Sileni, Vanna; Lebbe, Célèste; Mandalà, Mario; Millward, Michael; Arance, Ana; Bondarenko, Igor; Haanen, John B.A.G.; Hansson, Johan; Utikal, Jochen; Ferraresi, Virginia; Коваленко, Н. В.; Mohr, Peter; Probachai, V.; Schadendorf, Dirk; Nathan, Paul; Robert, Caroline; Ribas, Antoni; DeMarini, Douglas J.; Irani, Jhangir G.; Swann, S.; Legos, Jeffrey J.; Jin, Fan; Mookerjee, Bijoyesh; Flaherty, Keith T.

doi:10.1016/s0140-6736(15)60898-4

Cited by 1,198 publications

(983 citation statements)

References 14 publications

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“…The most common AE in the 12 patients in phase 1 and phase 2 combined were pyrexia, increased aspartate aminotransferase, peripheral edema, nasopharyngitis, increased blood alkaline phosphatase, stomatitis, erythema and headache. The relatively common AE in this Japanese study were also relatively common in clinical studies of dabrafenib and trametinib combination conducted in global studies 18, 24, 25. Similarly, the majority of AE observed in this Japanese study belong to grade 1 or 2, and it has been reported that the majority of AE were grade 1 or 2 in global clinical studies as well 18, 24, 25…”

Section: Discussionsupporting

confidence: 73%

“…The median duration of response was 32.1 weeks according to the investigator's assessment and 45 weeks according to the independent assessment. The median PFS has been reported to be 9.3–11.4 months and the median duration of response has been reported to be 9.2–13.8 months in clinical studies conducted to date 18, 24, 25. Thus, the median PFS and the duration of response in phase 1 were similar to the results of clinical studies conducted to date.…”

Section: Discussionsupporting

confidence: 60%

“…Pyrexia was the most common AE in our study and was also the most common AE in the global combination studies 18, 24, 25. Incidentally, pyrexia has been reported as a common AE with BRAF‐inhibitor monotherapy in the range of 16–26% when given as monotherapy 18, 19, 26, 27.…”

Section: Discussionsupporting

confidence: 55%

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Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Yamazaki¹,

Tsutsumida²,

Takahashi³

et al. 2018

The Journal of Dermatology

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The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionsupporting

confidence: 60%

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Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Yamazaki¹,

Tsutsumida²,

Takahashi³

et al. 2018

The Journal of Dermatology

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“…The combination of dabrafenib and trametinib was further investigated in two international phase III clinical trials: COMBI-d 62 and COMBI-v 63 . In COMBI-d 62 , 423 patients received either dabrafenib and trametinib, or dabrafenib and placebo; the ORR was 76% versus 54%, the median PFS was 11.0 months versus 8.8 months, and the median overall survival was 25.1 months versus 18.7 months (HR 0.71; P = 0.0107).…”

Section: Braf-targeted Therapiesmentioning

confidence: 99%

“…In COMBI-d 62 , 423 patients received either dabrafenib and trametinib, or dabrafenib and placebo; the ORR was 76% versus 54%, the median PFS was 11.0 months versus 8.8 months, and the median overall survival was 25.1 months versus 18.7 months (HR 0.71; P = 0.0107). Toxicity profiles were similar to those seen in previous trials of these agents, with febrile syndrome more common, and hyperkeratotic cutaneous manifestations less common in the combination group 62 . In COMBI-v 63 to BRAF monotherapy with vemurafenib (rather than with dabrafenib).…”

Section: Braf-targeted Therapiesmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors

et al. 2019

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Key Points Question What is the rate of cardiovascular adverse events among patients with melanoma treated with BRAF and MEK inhibitors compared with patients treated with BRAF inhibitor monotherapy? Findings In this systematic review and meta-analysis of 5 randomized clinical trials including 2317 patients, treatment with BRAF and MEK inhibitors was associated with a higher risk of pulmonary embolism, decrease in left ventricular ejection fraction, and arterial hypertension compared with treatment with BRAF inhibitor monotherapy. The risks of myocardial infarction, atrial fibrillation, and QTc prolongation were similar between groups. Meaning These findings demonstrate an association of cardiovascular adverse events with BRAF and MEK inhibitor therapy, which may guide clinical cardio-oncological management.

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Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial

Cited by 1,198 publications

References 14 publications

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors

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